The CB1, receptor family is primarily found in the central and peripheral nervous systems and to a lesser extent in several peripheral organs. The CB2 receptor is found primarily in the immune system. The pharmacology and therapeutic potential for cannabinoid receptor ligands has been reviewed (Exp. Opin. Ther. Patents 1998, 8, 301-313; Ann. Rep. Med. Chem., A. Doherty, Ed.; Academic Press, NY 1999, Vol. 34, 199-208; Exp. Opin. Ther. 2000, 10, 1529-1538; Trends in Pharma. Sci. 2000, 21, 218-224). CB1, receptor agonists have been associated with stimulation of feeding, anemetic properties, analgesia, reduction in intraocular pressure in glaucoma, and alleviation of muscle spasms in multiple sclerosis. Conversely, CB1 receptor antagonists have been shown effective for reducing feeding and body weight in animal models of obesity. However, most compounds that modulate CB1 receptor activity have the pharmacological property of inverse agonism which reduces basal CB1 receptor signal transduction as well as the activity of blocking CB1 agonist dependent receptor stimulation.
A number of selective, centrally acting CB1 receptor compounds are currently in development for the treatment of obesity. Nevertheless, there still remains a need for CB1 receptor compounds which have increased in vivo potency which are low molecular weight, and have pharmacokinetic and pharmacodynamic properties that provide therapeutic benefit while minimizing adverse events. See for example WO 2007/020502.
In addition to appentency disorders, CB1 inverse agonists have been shown to further potentiate the activity of antipsychotic agents in assays. Although current antipsychotic therapies are more or less effective at controlling positive symptoms, such therapies are not as effective in treating the negative and cognitive symptoms, rendering many patients incapable of leading normal lives. Convergent evidence suggests drugs that enhance neuronal activation in specific brain areas, hippocampal, striatal, and cortical areas in particular, would be effective in treating both negative and cognitive symptoms. In addition, the weight loss effects of CB1 receptor compounds have been demonstrated in animal models of antipsychotic treatment-induced weight gain and therefore may also be effective in controlling the treatment-emergent weight gain and metabolic syndrome seen with current antipsychotic therapies.
Moreover, CB1 receptor compounds have been shown to reduce alcohol consumption in animal models of alcohol drinking and therefore may be useful in the treatment of substance abuse.
While oral administration is a preferred route of drug delivery, many CB1 receptor compounds suffer from poor oral bioavailability as a consequence of their limited solubility in aqueous media and their metabolic lability. Because of the high lipophilicity of the endogenous cannabinoid ligands and the complementary site to which they bind in the CB1 receptor, known CB1 receptor compounds are also highly lipophilic. This high lipophilicity leads to poor solubility in aqueous media which limits oral absorption and bioavailability. See for example WO 2007/020502.
In addition, compounds which are rapidly metabolized by the liver may undergo metabolic conversion following absorption from the small intestine and prior to reaching the general circulation. During this process, reactive metabolic intermediate (s) may be formed and subsequently may react with other nucleophiles in the body (such as proteins, DNA, RNA, etc.). This could lead to toxicity issues. This so-called “first pass effect” also limits drug bioavailability. See for example WO 2007/020502.
In conclusion, there is a need for CB1 receptor compounds that have good bioavailability, have increased in vivo potency, are highly selective over CB2, are more readily soluble than previous molecules, and do not form reactive metabolites which could subsequently cause toxicity issues. The present invention satisfies this need and provides related advantages as well.